DESCRIPTION: (Applicant's Abstract) Transforming growth factor beta (TGF-beta) is one of a few polypeptide growth factors that negatively regulate the growth of various types of normal cells. Diminished or complete loss of autocrine TGF-beta activity is a hallmark in solid tumor progression. TGF-beta signal is transduced by a heteromeric complex of its type I (RI) and type II (RII) receptors present on cell surface. Studies showed that TGF-beta responsiveness is mainly due to down-regulation or mutation of one of the two receptors in various types of carcinomas. Studies have also showed that the expression of TGF-beta isoforms (termed beta 1, beta 2, and beta 3) is frequently up-regulated during tumor progression. Overexpression of TGF- beta 1 stimulated tumorigenicity of some TGF-beta-insensitive cancer cells suggesting that increased TGF-beta production with reduced receptor expression in cancer cells can render TGF-betas to act in a paracrine fashion on stroma to stimulate tumor growth. Currently, several mechanisms have been proposed to explain how paracrine TGF-beta might promote tumor progression. On the other hand, replacement of down- regulated or inactivated TGF-beta RI or RII restored autocrine TGF-beta growth inhibitory activity and suppressed tumorigenicity in a number of model systems including human breast and colon cancer cells, thus confirming that autocrine TGF-beta activity is tumor-suppressive in epithelial cancer cells. As such, it is conceivable that for the benefit of cancer therapy one should attempt to enhance autocrine TGF-beta activity while suppressing paracrine TGF-beta activity. In addition to RI and RII, TGF-betas also bind to another cell surface receptor called RIII that does not directly transduce TGF-beta signal. While RI/RII complex binds TGF-beta2 poorly, RIII has high affinity for all three isoforms. RIII has been shown to enhance TGF-beta binding to RI/RII complex suggesting that RIII may sequester TGF-beta to enhance its autocrine activity while abrogating its paracrine activity. Indeed, the applicant has recently reported that many human breast and colon cancer cells express reduced levels of RIII and re-expression of RIII enhanced autocrine TGF-beta activity and suppressed tumorigenicity in two breast cancer cell lines. Therefore, he hypothesizes that TGF-beta receptors, especially RIII, can be utilized to antagonize the paracrine tumor- promoting activity and enhance the autocrine tumor-suppressing activity of TGF-betas in breast and colon cancer cells so that their malignancy can be reverted. The applicant proposes to determine whether the extracellular domain of RIII and different TGF-beta receptor chimeras can be administered as drugs or delivered with gene therapy approaches to suppress tumorigenicity of cancer cells in mice. His goal is to determine whether these compounds are of potential use for cancer therapy.